The term "pathological hydrophobic interactions" means detrimental adhesion of components, including, but not limited to, cells and molecules in blood or other biological fluids thereby slowing or stopping the flow of blood or other biological fluid. The term "blood cell" means any cell or cell particle that circulates in the blood including, but not limited to, granulocytes, monocytes, erythrocytes, reticulocytes, platelets, and lymphocytes as well as precursor cells to the aforementioned cells. The term "fibrinolytic enzyme" means any enzyme that is capable of cleaving fibrin or capable of causing fibrin to be cleaved. The terms "isotonic" or "isoosmotic" solution are defined as solutions having the same osmotic pressure as blood. The terms clot, fibrin clot and thrombus are used interchangeably. The term "microcirculation" means blood circulation through blood vessels that are about 50 microns in diameter or less. The term "soluble fibrin" means soluble high molecular weight polymers of fibrinogen and fibrin. The term "biological fluids" means blood, lymph, or other fluids found in animals or humans. The term "ischemic tissue" is any tissue that is damaged from reduced blood flow. The term "anticoagulant" is any compound or agent that inhibits the blood coagulation process. The term "reperfusion injury" means injury to tissue or cells which occurs during reperfusion of damaged tissue with blood. The term "damaged tissue" means tissue damaged by ischemia, burns, toxins or other noxious insult.
It is to be understood that the citation of art contained herein is in no way to be construed as an admission that said art is suitable reference against the present patent application nor should this citation act as a waiver of any rights to overcome said art which may be available to the applicant.
A number of reports have described high amounts of fibrinogen and/or soluble fibrin in the blood of patients with thrombosis, impending thrombosis and many other diseases. These conditions include acute or chronic infection, severe trauma, burns, sickle cell crisis, malaria, leukemia, myocardial infarction, sepsis, shock, and almost any serious illness which produces tissue damage or surgical maneuvers. Evidence indicates that the high concentrations of fibrinogen and/or soluble fibrin may play an important role in the pathology of the conditions. Furthermore, much of the pathology that is encountered in disease may be due to pathological hydrophobic interactions which may be at least partially mediated by high concentration of fibrinogen and/or soluble fibrin.
What is needed is a means of decreasing the adverse effects of soluble fibrin. This would involve blocking the adhesion of soluble fibrin to cells in the circulation thereby blocking the aggregation of such cells and their adhesion or friction to vessel walls in the microvasculature. This would also decrease the risk of thrombosis.
Malaria is a disease caused by parasites of the genus Plasmodium of the class sporozoa in which the asexual cycle (schizogony) takes place in the red blood cells of vertebrates and the sexual cycle (sporogony) in mosquitoes. Members of genus which cause malaria in mammals and birds have closely similar morphology and life cycles. In humans, malaria is caused by four species: Plasmodium malariae, Plasmodium vivax, Plasmodium falciparum and Plasmodium ovale. Of these, Plasmodium falciparum causes the most severe disease, followed by Plasmodium vivax.
People become infected when mosquitoes inject sporozoites in the process of biting. The sporozoites travel to the liver where they develop into cryptozoic schizonts. In time, these are released from the liver as merozoites which infect red blood cells. The asexual merozoites in red blood cells develop through several stages which produce virtually all clinical disease. A portion of them form gametocytes which may be taken up by a mosquito to initiate the sexual stage of development and produce more sporozoites which are available for transmitting the infection to other individuals.
The number of parasites in the peripheral blood varies with the species of malaria. P. falciparum is the most serious infection and involves the highest number of infected erythrocytes, at times infecting 10 to 40% of all red blood cells.
The clinical manifestations of malaria are characterized by intermittent febrile paroxysms, secondary anemia and splenic enlargement..sup.1 It tends to progress from an acute to a chronic state. During the acute stage there are intermittent episodes. During the subsequent chronic stage, periods of latency are broken by a series of relapses similar to the acute primary attack. Malaria caused by P. falciparum tends to have few if any relapses, but produces a more severe acute infection with a higher percentage of parasitized erythrocytes.
The incubation period varies from 9 to 40 days for P. falciparum malaria, but may be much longer with the other types. Following this period, the patients undergo a prodromal period of a week or more when the number of parasites increases in the blood through the early asexual cycles. During this time, the patients will have no diagnostic clinical manifestations although lassitute, lack of appetite, vague pains in the bones and joints, and daily irregular fevers and chilliness, may be present. The disease may be confused with influenza or similar infections at this time.
The characteristic febrile paroxysms of malaria begin after the prodromal stage. The paroxysms begin with a cold stage or rigor of about an hour during which the patient has a shaking chill, although his temperature may be above normal. A hot stage of longer duration follows, in which the patient has a hot dry skin, flushed face and a temperature of 103.degree. to 106.degree. F., a full rapid pulse, headache, nausea, often vomiting and convulsions in young children. The patient perspires profusely, the temperature falls and the headache disappears so that in a few hours he is exhausted, but symptomless. The febrile paroxysm usually lasts 8 to 12 hours but is longer in P. falciparum infections. The paroxysm has been variously attributed to hemolysis from the destruction of red blood cells, shock from the free hemoglobin or metabolic products of the organisms. Virulence is often, but not always, correlated with the intensity of parasitemia. The periodicity of the fevers corresponds with the end of schizogonic cycle when the merozoites with their pigment and debris erupt from red blood cells into the blood stream.
A pernicious form of malaria may be observed in P. falciparum infections. Death from acute malaria is confined almost exclusively to this type disease. Victims may develop coma, convulsions and heart failure, with or without high fever. Pernicious infection is characterized by capillary obstruction of adhesive infected red blood cells and cerebral involvement. The cerebral type frequently assumes a comatose form with apathy, stupor and coma. However, it may be meningitic or encephalitic with delirium, psychotic disturbances, paralyses and convulsive seizures. Rapid collapse into coma is due to anoxia, cerebral edema, and increased cerebral pressure. In the septicemic infections, which may simulate a variety of diseases, there may be high fever, headache, delirium, symptoms of sun stroke, cyanosis and hemorrhages in the internal organs. When both the circulatory and nervous systems are involved, the disease may assume a fatal course with rapid loss of strength, cardiac weakness, collapse, and extensive internal hemorrhage.
In the natural course of malaria, the acute symptoms subside, relapses become fewer and latency develops. As a rule, P. falciparum infections disappear in less than one year and P. vivax infections in about 11/2 years although a few may last as long as 5 years or more.
The pathologic changes are primarily vascular. They include the destruction of red blood cells, blockage of the capillaries in the internal viscera and secondarily the anoxic impairment of the liver, brain and other organs. Each successive rupture of merozoites from red blood cells stimulates a humoral and cellular reaction resulting in the phagocytosis of parasitized, infected red blood cells, pigment and cellular debris. In primary P. vivax malaria, the red blood cells may show a 10 to 20 percent decrease, but in P. falciparum malaria greater destruction may take place. The marked anemia of malaria usually cannot be explained solely on the basis of destruction of infected red blood cells. Tissue anoxia is brought about by the reduction in red blood cells, multiple thrombosis of small blood vessels, and decreased circulating blood volume. The adhesiveness of infected erythrocytes and the changes in blood plasma cause clumping of red blood cells and adherence to the capillary and endothelial cells.
Serious circulatory disturbances, chiefly associated with P. falciparum infections, are produced through the blocking of the capillaries by clumped parasitized erythrocytes and phagocytes, increased whole blood and plasma viscosity, and slowing of the capillary circulation. The total plasma proteins, principally serum albumin, are reduced during acute infection, but the euglobulin, fibrinogen and gamma globulin are often increased. The erythrocyte sedimentation rate is increased during acute stages. In fatal P. falciparum infections, the brain is edematous, dark red and markedly congested. Microscopically, the cortex is dusty grey or brown and petechial hemorrhages may be visible in perivascular tissues. The cerebral tissues are filled with numerous infected red blood cells, pigmented parasites, pigment and phagocytes. The retarded circulation gives rise to microvascular thrombosis and anoxic necrosis of the perivascular tissues.
Cerebral malaria has certain clinical similarities to cerebral leukemia. In this condition, patients with acute leukemia with very high white blood cell counts which are frequently in excess of 100,000 cells per cubic mm develop signs of acute cerebral ischemia. This may be associated with coagulopathies, circulating soluble fibrin and increased whole blood viscosity in addition to physical rigidity of leukemic cells. If left untreated, this condition may cause death from cerebral ischemia before appropriate therapy for leukemia can be instituted.
What is needed is a therapy to increase blood flow through the brain or other ischemic tissues affected by diseases which cause abnormalities in circulating blood cells such as malaria and leukemia. This would prevent necrosis of tissue during an acute episode and buy time for definitive therapy aimed at the primary disease.